There is accumulating evidence that implicate the TNF superfamily members BLyS and APRIL, as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. BLyS and APRIL are expressed in B-cell non-Hodgkin lymphoma (NHL) and the expression of BLyS is associated with an aggressive disease phenotype. While it is clear that BLyS expression is required for normal B cell development and homeostasis, the exact source of BLyS in the normal and malignant scenario remains to be fully elucidated. Because serum BLyS levels are elevated in a number of B cell malignancies known to have a familial incidence, it is possible that dysregulation of BLyS occurs at the genetic level. The environmental, as well as genetic, requirements that mediate BLyS expression remain to be defined, and the promoter for the BLyS gene is poorly characterized. In preliminary work generated from our UI/MC Lymphoma SPORE Developmental Projects, we have found that a polymorphism in the BLyS promoter region correlates with increased serum BLyS levels in patients with B-cell malignancies, particularly those with a family history of B-cell related cancers. Wenow propose to follow-up these findings through a new,integrated basic andpopulation science project that utilizes the specimen and epidemiology resources developed through the UI/MC Lymphoma SPORE Biospecimens Core and the Molecular Epidemiology Resource(SPORE Project 5)during the first project period. We will determine if genetic variability in BLyS, the BLySreceptors TACI, BCMA, and BAFF-R, as well as the BLySrelated TNF molecule APRIL, are associatedwith the development of NHLand the clinical outcomeof patients. In addition to our genetic studies, wealso propose to determine the role of APRIL on thebiology of NHL B cells. We hypothesize that APRIL is involvedin the growth and survival of malignant B cells andbelieve that it maycontribute to thepathogenesis of NHL. Identification of patients who have or are predisposed to elevated BLyS and APRIL levels, or those who have genetic alterations in BLyS, APRIL, or their receptors, will provide us with an opportunity to better understand the significance of these molecules in B cell malignancies and ultimately to translate these findings to improved clinical management and perhaps novel therapeutic approaches.